Drug targeting is a potentially attractive new approach to killing malignant cells, which can leave normal tissue unharmed. A decisive breakthrough in drug targeting was the advent of hybridoma technology, making many monoclonal antibodies (MoAb) available in essentially limitless supply. To construct therapeutic reagents with selectivity for certain populations of tumor cells, MoAbs or other cell targeting proteins are linked to cytotoxic agents to form agents referred to as immunoconjugates, immunotoxins or fusion proteins which can combine the selectivity of the targeting moiety with the potency of the bioactive moiety. The choice of monoclonal antibody (or other targeting moiety) is based on the surface antigen profile of a malignant cell.
For the past decade, these types of biotherapeutic agents have been under investigation for the treatment of various cancers, and more recently for the treatment of immunological disorders such as rheumatoid arthritis and AIDS. Although these biotherapeutic agents have shown some potential to provide safe and effective therapy for human disease, many difficulties remain. Ideally, consistently locatable and reliable markers on target cells would permit the binding portion of biotherapeutic agents to completely avoid non-target tissue. In reality, cross-reactivity with antigens expressed by vital life-maintaining organs often gives rise to unacceptable complications in in vivo applications. There is also the potential that patients will demonstrate immune responses to the separate components of the biotherapeutic agents even though they may already be immunosuppressed by the course of their disease. Moreover, the cytotoxicity obtained in in vitro studies may be limited in clinical application due to a lack of potency in doses that can be tolerated by the patient. Finally, solid tumors are difficult to penetrate thoroughly and in hematologic malignancies, residual disease can cause relapse despite easier access to target cells in leukemias and lymphomas.
Fusion proteins specifically are designed to solve problems incurred in the use of immunoconjugates or immunotoxins, while providing some additional benefits. For example, the native toxin may be in a limited supply and thus, increasingly expensive. Furthermore, the production of immunotoxins or immunoconjugates by chemical coupling methods can result in reduced activity of either or both of the toxin or the antibody portion. Additionally, biotherapeutic agents prepared by chemically linking a whole antibody to a toxin are large in size, typically having a molecular mass of 210,000 kDa. Because of the large size, these biotherapeutic agents have limited vascular and tissue penetration; particularly, they cannot pass the blood-brain barrier. Finally, because the chemical conjugation methods used produce heterogeneous products, these types of biotherapeutic agents can illicit significant non-specific systemic toxicity. Also contributing to this non-specific systemic toxicity is the large molecule size of biotherapeutic agents and their resulting long half-life.
Thus, there are serious and recurring problems with these types of biotherapeutic agents and their associated therapies. Therefore, there is continuing need for improved biotherapeutic agents and methods of their use to target and inhibit or eliminate cell populations associated with various pathologies.